Tetrazole compounds and pharmaceutical agents containing such derivative as an active ingredient

Abstract

A tetrazole derivatives of formula (I) wherein R 1 is H, alkyl, alkoxy, carbocyclic ring, hetero ring, alkyl or alkoxy substituted by carbocyclic ring or hetero ring, etc.; AA 1 is bond or  AA 2 is bond or  AA 1 and AA 2 , together, may have the formula (a);  Y is the formula (b) (in which Tet ring is tetrazole; Z is alkylene, alkenylene, O, S, SO, SO 2 , NR 26 , methylene in alkylene replaced by O, S, —SO—, —SO 2 — or —NR 26 —; E is H, alkyl, COOR 27 or  in which Cyc is carbocyclic ring or hetero ring); a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof which has a pharmaceutical agents as an active ingredient. The compound of the formula (I) has an inhibitory effect on interleukin-1β converting enzyme, therefore, they are useful for prevention and/or treatment of various kinds of inflammatory disease.

What is claimed is:  
     
       1. A tetrazole derivative of formula (I), a non-toxic salt thereof, an acid addition salt thereof, or a hydrate thereof:                    
       wherein 
       R is a hydrogen atom,                    
       in which J is a bond, C1-6alkylene, C1-6oxyalkylene, C1-6aminoalkylene, C1-6thioalkylene, C2-6 alkenylene, carbocyclic ring or hetero ring, wherein the carbocyclic ring and hetero ring may be substituted by C1-4 alkyl with the proviso that when J contains an oxygen atom, a nitrogen atom or a sulfur atom, the ozygen atom, the nitrogen atom or the sulfur atom is bonded to C═O or S(O) m  group in R;  
       R 1  is  
       1) C1-8 alkyl,  
       2) C1-8 alkoxy,  
       3) C2-8 alkenyl,  
       4) C2-8 alkenyloxy,  
       5) C1-8 alkylamino,  
       6) di(C1-8 alkyl)amino,  
       7) C1-8 alkylthio,  
       8) Cyc 1  in which Cyc 1  is a carbocyclic ring or hetero ring, and Cyc 1  may be substituted by 1 to 5 substituents selected from the group consisting of a hydrogen atom, C1-8 alkyl, phenyl, phenyloxy, C1-8 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, keto, —OR 2 , —NR 2 R 3 , —S(O)R 2 , —SO 2 R 2 , —COOR 2  or —COR 2 , wherein R 2  is a hydrogen atom, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl, R 3  is a hydrogen atom, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl, C2-5 acyl, or R 2  and R 3 , taken together bonded to nitrogen atom, represent hetero ring,  
       9) Cyc 1 —O— wherein Cyc 1  is the same as hereinbefore defined,  
       10) Cyc 1 —S— wherein Cyc 1  is the same as herein before defined,  
       11) Cyc 1 —CO— wherein Cyc 1  is the same as hereinbefore defined,  
       12) C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino, di(C1-8 alkyl)amino or C1-8 alkylthio mono or di-substituted by Cyc 1 , Cyc 1 —O—, Cyc 1 —S—, or Cyc 1 —CO— wherein Cyc 1  is the same as hereinbefore defined,  
       13) trifluoromethyl,  
       14) Cyc 1 —CO—NH—CH 2 — wherein Cyc 1  is the same as hereinbefore defined,  
       15) amino,  
       16) benzyloxycarbonyl,  
       17) C2-5 acylamino, or  
       18) C1-8 alkoxy substituted by C1-8 alkoxy;  
       m is 0 or 1-2,  
       with the proviso that 
       (1) when m is 0, then —S(O) m — is not directly bonded to a nitrogen atom or a sulfur atom, and  
       (2) when m is 1, then —S(O) m — is not directly bonded to a sulfur atom;  
       AA 1  is  
       1) a bond or                    
        in which R 4  is  
       (1) a hydrogen atom,  
       (2) C1-8 alkyl,  
       (3) Cyc 2  in which Cyc 2  is a carbocyclic ring or hetero ring, and Cyc 2  may be substituted by 1 to 5 substituents selected from the group consisting of a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, tetrazole, —OR 5 , —NR 5 R 6 , —SR 5 , —COOR 5  or —COR 5 , wherein R 5  and R 6  each, independently, is a hydrogen atom, C1-4 allyl, phenyl or C14 alkyl substituted by phenyl, or  
       (4) C1-8 alkyl substituted by a substituent selected from —OR 7 , —NR 7 R 8 , —SR 7 , —COOR 7 , —COR 7 , —CONH 2 , —NR 7 —CO—NR 7 R 8 , guanidino or Cyc 2  in which R 7  and R 8  each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl and Cyc 2  is the same as hereinbefore defined;  
       AA 2  is  
       1) a bond or                    
        in which R 9  and R 10  each, independently, is  
       (1) a hydrogen atom,  
       (2) C1-8 alkyl,  
       (3) Cyc 3  in which Cyc 3  is a carbocyclic ring or hetero ring, and Cyc 3  may be substituted by 1 to 5 substituents selected from the group consisting of a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, tetrazole, —OR 11 , —NR 11 R 12 , —SR 11 , —COOR 11  or —COR 11 , wherein R 11  and R 12  each, independently, is a hydrogen atom, C1-4 alkyl phenyl or C1-4 alkyl substituted by phenyl,  
       (4) C1-8 alkyl substituted by a substituent selected from —OR 13 , —NR 13  R 14 , —SR 13 , —COOR 13 , —COR 13 , —CONH 2 , —NR 13 —CO—NR 13 R 14 , guanidino or Cyc 3  in which R 13  is a hydrogen atom, C1-alkyl, phenyl or C1-4 alkyl substituted by phenyl, R 14  is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 alkyl substituted by phenyl, t-butyloxycarbonyl or benzyloxycarbonyl and Cyc 3  is the same as hereinbefore defined or  
       (5) R 9  and R 10 , together, are a C1-6 alkylene or C2-6 alkenylene;  
       AA 1  and AA 2 , together, may have the formula:                    
       in which R 15  and R 16  each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl with the proviso that C1-4 alkyl or phenyl may be substituted by C1-4 alkyl, C1-4 alkoxy, a halogen atom, trifluoromethyl or phenyl;  
       R 17  is  
       (1) a hydrogen atom,  
       (2) C1-8 alkyl,  
       (3) Cyc 3  in which Cyc 3  has the same meaning as hereinbefore defined or  
       (4) C1-8 alkyl substituted by a substituent selected from —OR 13 , —NR 13 R 14 , —SR 13 , —COOR 13 , —COR 13 , —CONH 2 , —NR 13 —CO—NR 14 , guanidino or Cyc 3  in which R 13 , R 14  and Cyc 3  are the same as hereinbefore defined;  
       q is 2-12,  
       with the proviso that a carbon atom in —(CH 2 ) q — may be replaced by an oxygen atom, sulfur atom, —SO—, —SO 2 — or —NR 18 — in which R 18  is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl, or two hydrogen atoms at ortho positions are replaced by a double bond, and  
       Y is                    
       in which R 19  is a hydrogen atom, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl;  
       n is 1-4;                    
        or                    
       Z is  
       1) C1-6 alkylene,  
       2) C2-6 alkenylene,  
       3) oxygen atom,  
       4) sulfur atom,  
       5) —CO—,  
       6) —SO—,  
       7) —SO 2 —,  
       8) —NR 26 — in which R 26  is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 alkyl substituted by phenyl, or  
       9) a carbon atom in C1-6 alkylene replaced by an oxygen atom, sulfur atom, —CO—, —SO—, —SO 2 — or —NR 26 — in which R 26  is the same as hereinbefore defined, with the proviso that Z is bonded directly to the carbon atom on a tetrazole ring;  
       E is (1) a hydrogen atom, (2) a halogen atom, (3) C1-4 alkyl, (4) —COOR 27  in which R 27  is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 substituted by phenyl, (5) —CONR 28 R 29  in which R 28  and R 29  each, independently, is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 substituted by phenyl or R 28  and R 29 , taken together, bonded to nitrogen atom represent hetero ring or —NR 28 R 29  in which R 28  and R 29  are the same as hereinbefore defined, or                    
        in which                    
        is a carbocyclic ring or hetero ring, substituted by —(R 20 ) p  wherein  
       R 20  is  
       1) a hydrogen atom,  
       2) C1-8 alkyl,  
       3) a halogen atom,  
       4) nitro,  
       5) trifluoromethyl,  
       6) nitrile,  
       7) —OR 22 ,  
       8) —NR 22 R 23 ,  
       9) —SR 22 ,  
       10) —COOR 22 ,  
       11) —COR 22    
       12) —CONR 28 R 29  in which R 28  and R 29  are the same as hereinbefore defined,  
       13) Cyc 4  in which Cyc 4  is a carbocyclic ring or hetero ring, and Cyc 4  may be substituted by 1 to 5 substituents selected from the group consisting of a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, tetrazole, —OR 24 , —NR 24 R 25 , —SR 24 , —COOR 24  or —COR 24  in which R 24  and R 25  each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl, or  
       14) C1-8 alkyl substituted by Cyc 4  in which Cyc 4  is the same as hereinbefore defined, R 22  is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl, R 23  is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C2-5 acyl or trifluoromethylcarbonyl;  
       p is 1-5; or  
       —Z—E is a halogen atom, trifluoromethyl, C1-4 alkyl di-substituted by phenyl or tri(C1-4 alkyl) silyl with the proviso that  
       (1) when Z is C1-6 alkylene or C2-6 alkenylene, E is now a hydrogen atom or C1-4 alkyl,  
       (2) when Z is —SO—, E is not a hydrogen atom, or  
       (3) at least one of J, Cyc 1 , Cyc 2 , Cyc 3 , Cyc 4 , and                    
       represents a hetero ring, 
       (4) when J, Cyc 1 , Cyc 2 , Cyc 3 , Cyc 4  and                    
        represent a carbocyclic ring at the same time, then R 2  and R 3 , taken together bonded to nitrogen atom represents hetero ring,  
       (5) when J, Cyc 1 , Cyc 2 , Cyc 3 , Cyc 4  and                    
        represent a carbocyclic ring at the same time, then R 28  and R 29 , taken together bonded to nitrogen atom, represent hetero ring,  
       (6) when J, Cyc 1 , Cyc 2 , Cyc 3 , Cyc 4  and                    
        represent a carbocyclic ring at the same time, then R 9  and R 10 , together are a C1-6 alkylene or C2-6 alkenylene, or  
       (7) when J, Cyc 1 , Cyc 4  and                    
        represent a carbocyclic ring at the same time, then AA 1  and AA 2 , together, may have the formula;                    
     
     
       2. The compound according to  claim 1 , wherein the E group in Y is a hydrogen atom, halogen atom, C1-4 alkyl, —CO OR 27 , CONR 28 R 29  or —NR 28 R 29  in which R 27 , R 28  and R 29  are defined as in  claim 1 . 
     
     
       3. The compound according to  claim 1 , wherein the E group in Y is                    
       in which R 20  and p are defined as in  claim 1 , and                    
       is a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring. 
     
     
       4. The compound according to  claim 1 , wherein the E group in Y is                    
       in which R 20  and p are defined as in  claim 1 , and                    
       is a 5-18 membered mono-cyclic, bi-cyclic or tri-cyclic hetero ring containing 1-3 nitrogen atoms, one oxygen atom or one sulfur atom. 
     
     
       5. The compound according to  claim 1 , wherein the —Z—E group in Y is a halogen atom, trifluromethyl, diphenylmethyl or tri(C1-alkyl)silyl. 
     
     
       6. The compound according to  claim 1 , wherein AA 1  is α-amino acid residue and AA 2  is α-amino acid residue. 
     
     
       7. The compound according to  claim 1 , wherein AA 1  is a bond and AA 2  is α-amino acid residue. 
     
     
       8. The compound according to  claim 1 , wherein AA 1  is a bond and AA 2  is a bond. 
     
     
       9. The compound as in any one of  claims 1  to  3 , wherein AA 1  and AA 2  taken together, represent                    
       in which R 15 , R 16 , R 17  and q are defined as in  claim 1 . 
     
     
       10. A compound according to  claim 1 , which is 
       (1) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(1-methylpyrrol-2-yl methyl) tetrazol-2-yl)pentanoic acid,  
       (2) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(1-methylpyrrol-2-ylmethyl) tetrazol-1-yl)pentanoic acid,  
       (3) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(pyridin-2-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (4) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(pyridin-2-ylmethyl)tetrazol-1-yl)pentanoic acid,  
       (5) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(pyridin-3-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (6) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(pyridin-3-ylmethyl)tetrazol-1-yl)pentanoic acid,  
       (7) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(pyridin-4-yl)tetrazol-2-yl) pentanoic acid,  
       (8) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(pyridin-4-yl)tetrazol-1-yl) pentanoic acid,  
       (9) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(1l-methylpyrimidin-2,4-dion-3-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (10) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(1-methylpyrimidin-2,4-dion-3-ylmethyl)tetrazol-1-yl)pentanoic acid,  
       (11) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(imidazol-1-ylmethyl) tetrazol-2-yl)pentanoic acid,  
       (12) N-benzyloxycarbonyl-3-amino-4-o -(5-(imidazol-1-ylmethyl) tetrazol-1-yl)pentanoic acid,  
       (13) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(thiophen-2-yl)tetrazol-2-yl) pentanoic acid,  
       (14) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(thiazo-2-yl)tetrazol-1-yl) pentanoic acid,  
       (15) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(thiazo-3-yl)tetrazol-2-yl) pentanoic acid,  
       (16) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(thiazo-3-yl)tetrazol-1-yl) pentanoic acid,  
       (17) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(3-imidazol-1-ylpropyl) tetrazol-2-yl)pentanoic acid,  
       (18) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(3-imidazol-1-ylpropyl) tetrazol-1-yl)pentanoic acid,  
       (19) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2,2,6,6-tetramethylpiperidin-2-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (20) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2,2,6,6-tetramethylpiperidin-1-ylmethyl)tetrazol-1-yl)pentanoic acid,  
       (21) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(benzoimizazol-2-ylmethyl) tetrazol-2-yl)pentanoic acid,  
       (22) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(benzoimizazol-2-ylmethyl) tetrazol-1-yl)pentanoic acid,  
       (23) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(benzothiazol-2-ylmethyl) tetrazol-2-yl)pentanoic acid,  
       (24) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(benzothiazol-2-ylmethyl) tetrazol-1- yl)pentanoic acid,  
       (25) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(thiazol-2-ylthio)tetrazol-2-yl)pentanoic acid,  
       (26) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(thiazol-2-ylthio)tetrazol-1-yl)pentanoic acid,  
       (27) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(5-imidazol-1-ylpentyl) tetrazol-2-yl)pentanoic acid,  
       (28) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(5-imidazol-1-ylpentyl) tetrazol-1-yl)pentanoic acid,  
       (29) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(4-fluorophenyl)thiazol-2-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (30) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(4-fluorophenyl)thiazol-2-ylmethyl)tetrazol-1-yl)pentanoic acid,  
       (31) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(4-chlorophenyl)thiazol-2-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (32) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(4-chlorophenyl)thiazol-2-ylmethyl)tetrazol-1-yl)pentanoic acid,  
       (33) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(3-nitrophenyl)thiazol-2-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (34) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(3-nitrophenyl)thiazol-2-ylmethyl)tetrazol-2-yl)pentanoic acid,  
       (35) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(imizazol-4-ylmethyl) tetrazol-2-yl)pentanoic acid,  
       (36) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(imizazol-4-ylmethyl) tetrazol-1-yl)pentanoic acid,  
       (37) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2-(imidazol-2-yl)ethenyl) tetrazol-2-yl)pentanoic acid,  
       (38) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2-(imidazol-2-yl)ethenyl) tetrazol-1-yl)pentanoic acid,  
       (39) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2-(imidazol-2-yl)ethyl) tetrazol-2-yl)pentanoic acid,  
       (40) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2-(imidazol-2-yl)ethyl) tetrazol-1-yl)pentanoic acid,  
       (41) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(imidazol-2-ylmethyl) tetrazol-2-yl)pentanoic acid, or  
       (42) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(imidazol-2-ylmethyl) tetrazol-1-yl)pentanoic acid,  
       an ester thereof, a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof. 
     
     
       11. A compound according to  claim 1 , which is 
       (1) 3-(N-(2S-(2-phenyl-4R-methyl-4,5-dihydrothiazol-4-ylcarbonylamino) propionyl)amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (2) 3-(N-(2S-(2-phenyl-4,5-dihydrothiazol-4-ylcarbonylamino)propionyl) amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (3) (N-(1-benzyloxycarbonylpiperidin-2S-ylcarbonyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (4) N-(1-acetylpiperidin-2S-ylcarbonyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (5) N-(1-benzyloxycarbonylpyrrolidin-2S-ylcarbonyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid, or  
       (6) N-(1-acetylpyrrolidin-2S-ylcarbonyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid, or  
       and ester thereof, a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof. 
     
     
       12. A compound according to  claim 1 , which is 
       (1) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(3-(imidazol-2-yl) phenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (2) N-benzyloxycarbonyl-3-amino-4oxo-5-(5-(3-(imidazol-2-yl) phenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (3) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(imidazol-2-yl)phenylmethyl)tetrazol-2-yl) pentanoic acid,  
       (4) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(4-(imidazol-2-yl)phenylmethyl)tetrazol-2-yl) pentanoic acid,  
       (5) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2-(imidazol-2-yl)phenylmethyl)tetrazol-2-yl) pentanoic acid,  
       (6) N-benzyloxycarbonyl-3-amino-4-oxo-5-(5-(2-(imidazol-2-yl)phenylmethyl)tetrazol-2-yl) pentanoic acid,  
       (7) N-(2-(thiazo-2-yl)ethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-2-yl)pentanoic acid,  
       (8) N-(2-(thiazo-2-yl)ethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl tetrazol-1-yl)pentanoic acid,  
       (9) N-(2-(pyridin-2-yl)ethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (10) N-(2-(pyridin-2-yl)ethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylthio)tetrazol-2-yl)pentanoic acid,  
       (11) N-2-(4-methylthiazol-5-yl)ethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylthio)tetrazol-2-yl)pentanoic acid,  
       (12) N-(2-(4-methyl-1-thiazo1-5-yl)ethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylthio)tetrazol-1-yl)pentanoic acid,  
       (13) N-(2-phenylethylthio)carbonyl-3-oxo-4-oxo-5-(5-(4-(pyrrolidin-1-ylmethyl)phenylthio)tetrazol-2-yl)pentanoic acid,  
       (14) N-(2-phenylethylthio)carbonyl-3-amino-4-oxo-5-(5-(4-(pyrrolidin-1-ylmethyl)phenylthio)tetrazol-2-yl)pentanoic acid,  
       (15) N-(2-(4-methylthiazol-5-yl)ethylthio)carbonyl-3-amino4-oxo-5-(5-(2,6-dichlorophenylthio)tetrazol-2-yl)pentanoic acid,  
       (16) N-(2-(4methylthiazol-5-yl)ethylthio)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylthio)tetrazol-1-yl)pentanoic acid,  
       (17) N-3-(pyrimidin-2-yl)propyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylthio)tetrazol-2-yl)pentanoic acid,  
       (18) N-3-(pyrimidin-2-yl)propyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylthio) tetrazol-1-yl)pentanoic acid,  
       (19) N-(thiazo-4-ylcarbonyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (20) N-perhydrobenzo-1,4-diazepin-2,5-dion-3-ylcarbonyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (21) N-(2-hexahydro-2-oxo-azepin-1-yl)propionyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (22) N-(2S-(tetrahydro-5-oxo-1,4-benzooxsazepin-4-yl)propionyl)-3-amino4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (23) N-(2S-(2,3-indol-3,4-tetrahydro-2-oxoazepin-1-yl)propionyl)-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (24) N-(pyridin-4-ylmethyloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-2-yl)pentanoic acid,  
       (25) N-(tetrahydrofuran-3-yloxy)carbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-2-yl)pentanoic acid,  
       (26) N-(quinolin-8-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (27) N-(thiazo-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl) pentanoic acid,  
       (28) N-(5-(pyridin-2-yl)thiazo-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (29) N-1-(3chloro-5-trifluoromethylpyridin-2-yl)pyrrol-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (30) N-(2-acetylamino-4-methylthiazol-5-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid  
       (31) N-(benzofurazan-4-yl)sulfonyl-3-amino-4-oxo-5-(5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (32) N-(3,5dimethylisooxazol-4-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-2-yl)pentanoic acid,  
       (33) N-(1,1-dioxotetrahydrothiophen-3-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (34) N-(5-phenylcarbonylaminomethylthiophen-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (35) N-(2,1,3-benzothiadiazol-4-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-2-yl)pentanoic acid,  
       (36) N-(6-chloroimizazo[2,1-B]thiazol-5-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (37) N-(5-(2-methylthiopyrimidin4yl)thiazo-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (38) N-5-(isooxazol-3-yl)thiazo-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (39) N-(5-(4-chlorophenylcarbonylaminomethyl)thiazo-2-yl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (40) N-4-(pyrrolidin-1-yl)phenyl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-1-yl)pentanoic acid, or  
       (41) N-4-(morpholin-4-yl)phenyl)sulfonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl) tetrazol-1-yl)pentanoic acid, or  
       an ester thereof, an non-toxic salt thereof, an acid addition salt thereof or hydrate thereof. 
     
     
       13. A compound according to  claim 1 , which is 
       (1) 3-(N-(2-(hexahydro-2-oxo-3S-(phenylcarbonylamino)azepin-1-yl)) propionyl)amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (2) 3-(N-(2-(hexahydro-2-oxo-3S-(phenylcarbonylamino)azepin-1-yl)) propionyl)amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-2-yl)pentanoic acid,  
       (3) 3-(N-(2-(hexahydro-2-oxo-3S-(phenylcarbonylamino)azepin-1-yl)) propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (4) 3-(N-(2-(hexahydro-2-oxo-3S-(thiazol-4-ylcarbonylamino)azepin-1-yl)) propionyl)amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl)pentanoic acid,  
       (5) 3-(N-(2-(hexahydro-2-oxo-3S-(thiazol-4-ylcarbonylamino)azepin-1-yl)) propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (6) 3-(N-(2-(hexahydro-2-oxo-3S-(pyridin-3-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (7) 3-(N-(2-(hexahydro-2-oxo-3S-(quinolin-2-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (8) 3-(N-(2-(hexahydro-2-oxo-3S-(pyridin-2-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (9) 3-(N-(2-(hexahydro-2-oxo-3S-(morpholin-1-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (10) 3-(N-(2-(hexahydro-2-oxo-3S-(pyridin-4-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (11) 3-(N-(2-(hexahydro-2-oxo-3S-(4-methoxyphenylcarbonylamino) azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (12) 3-(N-(2-(hexahydro-2-oxo-3S-(3-methoxyphenylcarbonylamino) azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (13) 3-(N-(2-(hexahydro-2-oxo-3S-(4-(morpholin-1-ylcarbonyl) phenylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (14) 3-(N-(2-(hexahydro-2-oxo-3S-(quinolin-3-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (15)  3 -(N-(2-(hexahydro-2-oxo-3S-(pyridin-3-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl) pentanoic acid,  
       (16) 3-(N-(2-(hexahydro-2-oxo-3S-(4-dimethylaminophenylcarbonylamino) azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (17) 3-(N-(2-(hexahydro-2-oxo-3S-(3-carboxyphenylcarbonylamino) azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (18) 3-(N-(2-(hexahydro-2-oxo-3S-(4-carboxyphenylcarbonylamino) azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid,  
       (19) 3-(N-(2-(hexahydro-2-oxo-3S-(imidazol-5-ylcarbonylamino)azepin-1-yl))propionyl)amino-4-oxo-5-(5-phenylmethyltetrazol-1-yl)pentanoic acid, or  
       (20) N-(2-(4-fluorophenyl)-4-oxo-5-benzyloxocarbonylaminopyrimidin-3-yl) methylcarbonyl-3-amino-4-oxo-5-(5-(2,6-dichlorophenylmethyl)tetrazol-1-yl) pentanoic acid.  
     
     
       14. A compound according to  claim 1 , which is 
       3-(N-(2-(hexahydro-2-oxo-3S-(phenylcarbonylamino)azepin-1-yl))propionyl) amino-4-oxo-5-(5-trifluoromethyltetrazol-2-yl) pentanoic acid, or  
       and ester thereof, a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof. 
     
     
       15. A pharmaceutical composition which comprises, as an active ingredient, an effective amount of a compound of formula (1) according to  claim 1 , a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof, and a pharmaceutically acceptable carrier or coating. 
     
     
       16. A method for the prevention and/or the treatment in a patient of diseases induced by interleukin-1β converting enzyme, which comprises the administration to a patient of an effective amount of a compound of formula (I) according to  claim 1 , a non-toxic salt thereof, a non-toxic acid addition salt thereof or hydrate thereof. 
     
     
       17. A method for the prevention and/or the treatment in a patient of insulin dependent diabetes (type I), multiple sclerosis, acute or delayed type hypersensitivity, infectious diseases, infectious complications, septic shock, arthritis, colitis, glomelular nephritis, hepatitis, hepatic cirrhosis, pancreatitis, reperfusion injury, cholangeitis, encephalitis, endocarditis, myocarditis, vasculitis, Alzheimer's disease, Parkinson's disease, dementia, cerebral vascular disturbance, neuro-degenerative diseases, bone or cartilage-resorption disease, AIDS, ARC (AIDS) related complex), adult T cell leukemia, hairy cell (pilocytic) leukemia, myelosis, respiratory dysfunction, arthropathy, uveitis, neoplasm, diffuse collagen diseases, ulcerative colitis, Sjogren's syndrome, primary biliary cirrhosis, idiopathic thrombocytopnic purpura, autoimmonohaemolytic anemia, severe myasthenia, osteodisplasia syndrome, periodic thrombocytopenia, aplastic anemia, idiopathic thrombocytopenia, diseases accompanied with thrombocytopenia, adult dyspnea syndrome, hyperplasia of the prostatic gland, myaoma of the uterus, asthma bronchial, arteriosclerosis, congenital teratoma, nephritis, senile cataract, chronic fatigue syndrome, myodystrophy or peripheral nervous disturbance, which comprises the administration to a patient of an effective amount of a compound of formula (I) according to  claim 1 , a non-toxic salt thereof, a non-toxic acid addition salt thereof or a hydrate thereof.